Acetic acid ester compound or salt thereof

ABSTRACT

An acetic acid ester compound represented by the following formula (I) or a salt thereof, 
                         
wherein R represents optionally substituted deuterated lower alkyl, is disclosed.

This application is a divisional of U.S. Ser. No. 14/370,544, filed Jul.3, 2014, which is a 35 U.S.C. 371 National Phase Entry Application fromPCT/JP2013/051533, filed Jan. 25, 2013, which claims the benefit ofJapan Patent Application No. 2012-016685 filed on Jan. 30, 2012, thedisclosures of which are incorporated herein in its entirety byreference.

TECHNICAL FIELD

The present invention relates to an acetic acid ester compound or a saltthereof that is useful for a prophylactic and/or therapeutic agent for adisease that is expected to be ameliorated by an increase inintraurethral pressure, such as stress urinary incontinence.

BACKGROUND ART

Urinary incontinence is involuntary leakage of urine, and pathologicalurinary incontinence is a condition in which objective leakage, which isa social or hygienic problem, is observed. Stress urinary incontinenceis leakage of urine upon a rise in abdominal pressure, such as duringcoughing, sneezing, laughing, or exercising, despite the absence ofbladder contraction. Stress urinary incontinence has two main causes.One is hypermobility of the bladder neck and urethra. Descent of thebladder neck due to pelvic floor relaxation causes poor transmission ofabdominal pressure to the urethra. Thus, upon a rise in abdominalpressure, only intravesical pressure is increased, resulting in leakageof urine. The other is intrinsic sphincter deficiency, leakage of urineupon a rise in abdominal pressure due to reduced sphincter function.Examples of the causes thereof include childbirth, obesity, aging,menopause, and pudendal nerve injury. Stress urinary incontinence is themost common type of urinary incontinence, and is reportedly observed inabout 50% of female patients with urinary incontinence (Non-patentLiterature 1). Urinary incontinence has significant adverse effects onwomen physically, mentally, and socially; inhibits participation insports or social activities; and becomes a factor that decreases thequality of daily life (QOL). As a result, patients with stress urinaryincontinence are made to suffer in their daily lives.

In recent years, duloxetine, a serotonin-noradrenaline reuptakeinhibitor (SNRI), has been developed and used as a new therapeutic agentfor stress urinary incontinence in Europe. However, since duloxetinealso has an antidepressant action, and there are concerns about sideeffects such as suicide (Non-patent Literature 2), duloxetine has notbeen approved as a therapeutic agent for stress urinary incontinence inother countries, including the U.S. and Japan. Therefore, there is ademand for the development of drugs that are useful for stress urinaryincontinence.

Patent Literature 1 to 3 describe acetic acid ester compounds.

CITATION LIST Patent Literature

-   PTL 1: JPS62-051242B-   PTL 2: JP2004-534802A-   PTL 3: JPS62-039567A

Non-Patent Literature

-   NPL 1: Int Urogynecol J Pelvic Floor Dysfunct (2000), 11 (5),    301-319-   NPL 2: Bmj (2005), 330 (7488), 396

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a drug that is usefulfor a disease that is expected to be ameliorated by an increase inintraurethral pressure, such as stress urinary incontinence.

Solution to Problem

The present inventors conducted extensive research on compounds havingan effect of ameliorating stress urinary incontinence, and found that anacetic acid ester compound represented by the following formula (I) hasan intraurethral pressure-increasing action. The inventors conductedfurther research, and accomplished the present invention.

The present invention provides the following acetic acid ester compoundor a salt thereof and a prophylactic and/or therapeutic agent for adisease that is expected to be ameliorated by an increase inintraurethral pressure, such as stress urinary incontinence, the agentcomprising the acetic acid ester compound or a salt thereof as an activeingredient.

-   Item 1. An acetic acid ester compound represented by the following    formula (I) or a salt thereof,

wherein R represents optionally substituted deuterated lower alkyl.

-   Item 2. The acetic acid ester compound according to item 1 or a salt    thereof, wherein R represents deuterated straight C₁₋₆ alkyl.-   Item 3. The acetic acid ester compound according to item 1 or 2 or a    salt thereof, wherein R represents n-propyl in which 2 to 7 of the    hydrogen atoms are replaced by deuterium.-   Item 4. The acetic acid ester compound according to any of items 1    to 3 or a salt thereof, wherein R represents propyl-2,2,3,3,3-d5,    propyl-1,1,2,2,3,3,3-d7, propyl-1,1-d2, propyl-2,2-d2,    propyl-3,3,3-d3, or propyl-1,1,2,2-d4.-   Item 5. An acetic acid ester compound of any of the following (a) to    (f), or a salt thereof:    -   (a) 4-piperidinyl 2,2-diphenyl-2-(propoxy-2,2,3,3,3-d5)acetate,    -   (b) 4-piperidinyl        2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetate,    -   (c) 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1-d2)acetate,    -   (d) 4-piperidinyl 2,2-diphenyl-2-(propoxy-2,2-d2)acetate,    -   (e) 4-piperidinyl 2,2-diphenyl-2-(propoxy-3,3,3-d3)acetate, and    -   (f) 4-piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2-d4)acetate.-   Item 6. A pharmaceutical composition comprising an effective amount    of the acetic acid ester compound according to any of items 1 to 5    or a salt thereof, and a pharmaceutical carrier.-   Item 7. A prophylactic and/or therapeutic agent for a disease that    is expected to be ameliorated by an increase in intraurethral    pressure, the agent comprising an effective amount of the acetic    acid ester compound according to any of items 1 to 5 or a salt    thereof, and a pharmaceutical carrier.-   Item 8. A prophylactic and/or therapeutic agent for stress urinary    incontinence, the agent comprising an effective amount of the acetic    acid ester compound according to any of items 1 to 5 or a salt    thereof, and a pharmaceutical carrier.-   Item 9. A method for preventing and/or treating a disease that is    expected to be ameliorated by an increase in intraurethral pressure,    the method comprising administering an effective amount of the    acetic acid ester compound according to any of items 1 to 5 or a    salt thereof.-   Item 10. The method according to item 9, wherein the disease that is    expected to be ameliorated by an increase in intraurethral pressure    is stress urinary incontinence.-   Item 11. The acetic acid ester compound according to any of items 1    to 5 or a salt thereof for preventing and/or treating a disease that    is expected to be ameliorated by an increase in intraurethral    pressure.-   Item 12. Use of the acetic acid ester compound according to any of    items 1 to 5 or a salt thereof for preventing and/or treating a    disease that is expected to be ameliorated by an increase in    intraurethral pressure.-   Item 13. Use of the acetic acid ester compound according to any of    items 1 to 5 or a salt thereof for the production of a prophylactic    and/or therapeutic agent for a disease that is expected to be    ameliorated by an increase in intraurethral pressure.

Advantageous Effects of Invention

The present invention provides an acetic acid ester compound representedby formula (I) above or a salt thereof, which is useful as a therapeuticagent for stress urinary incontinence.

It has been revealed that the acetic acid ester compound or a saltthereof of the present invention exhibits an excellent intraurethralpressure-increasing action in vivo. Accordingly, the acetic acid estercompound or a salt thereof of the present invention can be expected tohave efficacy that is effective as a prophylactic and/or therapeuticagent for a disease that is expected to be ameliorated by an increase inintraurethral pressure, such as stress urinary incontinence.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows changes in urethral baseline pressure 8 hours afteradministration of test substances.

DESCRIPTION OF EMBODIMENTS

The acetic acid ester compound of the present invention is an aceticacid ester compound represented by the following formula (I) or a saltthereof,

wherein R represents optionally substituted deuterated lower alkyl.

The acetic acid ester compound of the present invention, which isrepresented by formula (I) above, is a novel compound that is notspecifically disclosed in, for example, the aforementioned literature.

For example, Patent Literature 1 (JPS62-051242B) discloses anα,α-diphenyl-α-alkoxyacetic acid-1-methyl-4-piperidyl ester derivativeas a compound that can effectively treat hypertonic functional states inthe region of the bladder; however, this compound differs from thecompound of the present invention in that it has methyl at the1-position of piperidine and is not deuterated, and did not have asignificant effect on urethral baseline pressure, as shown in the TestExample (Comparative Example 1) described later.

Patent Literature 2 (JP2004-534802A) discloses deuterated N- andα-substituted diphenyl alkoxy acetic acid aminoalkyl esters that areuseful as pharmaceutical preparations for treating hypertonic functionalstates; however, they differ from the compound of the present inventionin that they have methyl at the 1-position of piperidine, and did nothave a significant effect on urethral baseline pressure, as shown in theTest Example (Comparative Example 2) described later.

Further, Patent Literature 3 (JPS62-039567A) discloses a benzilic acid 4piperidyl ester derivative having a bladder capacity-increasing action.However, this compound differs from the compound of the presentinvention in that it is not deuterated, and did not have a significanteffect on urethral baseline pressure, as shown in the Test Example(Comparative Example 3) described later.

In the present specification, the lower alkyl of “optionally substituteddeuterated lower alkyl” represented by R is straight or branched C₁₋₆alkyl. Examples thereof include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and thelike. Straight C₁₋₆ alkyl is preferable, and n-propyl is morepreferable.

Examples of substituents of “optionally substituted deuterated loweralkyl” represented by R include halogen atoms (fluorine atom, chlorineatom, bromine atom, iodine atom), hydroxyl, cyano, amino, nitro, oxo,carboxyl, carbamoyl, cycloalkyl (such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl), alkenyl (such as vinyl, 1- or 2-propenyl,and 1-butenyl), alkynyl (such as ethynyl, 1- or 2-propynyl, 1-, 2-, or3-butynyl, and 1-methyl-2-propynyl), alkoxy (such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy,isopentyloxy, and hexyloxy), acyl (such as formyl, acetyl, propionyl,butyryl, isobutyryl, and benzoyl), acyloxy (such as formyloxy,acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, and benzoyloxy),alkoxycarbonyl (such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, andhexyloxycarbonyl), saturated heterocyclic groups (such as azetidino,pyrrolidino, imidazolidino, oxazolidino, thiazolidino, piperazino,piperidino, morpholino, and thiomorpholino), unsaturated heterocyclicgroups (such as furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolyl, quinolyl, isoquinolyl,benzo[b]thienyl, and benzimidazolyl), aromatic hydrocarbon groups (suchas phenyl, naphthyl, tolyl, xylyl, anthracenyl, phenanthrenyl, andbiphenylyl), alkylamino (such as methylamino, ethylamino, n-propylamino,isopropylamino, n-butylamino, isobutylamino, sec-butylamino,tert-butylamino, n-pentylamino, and n-hexylamino), acylamino (such asformylamino, acetylamino, propionylamino, butyrylanimo, isobutyrylamino,and benzoylamino), aralkyloxy (such as benzyloxy, phenethyloxy,phenylpropyloxy, and naphthylmethyloxy), and the like. Hydroxyl ispreferable. When such substituents are present, the number thereof istypically one to three.

In the present specification, the term “deuterated” indicates that oneto all of the hydrogen atoms of R are replaced by deuterium, andpreferably indicates that two to seven of the hydrogen atoms of R arereplaced by deuterium.

The optionally substituted deuterated lower alkyl is particularlypreferably propyl-2,2,3,3,3-d5, propyl-1,1,2,2,3,3,3-d7, propyl-1,1-d2,propyl-2,2-d2, propyl-3,3,3-d3, or propyl-1,1,2,2-d4.

The acetic acid ester compound of the present invention can be producedaccording to reaction scheme 1 below.

(R is the same as above.)

The compound represented by formula (I) can be obtained by reacting thecompound represented by formula (1a) with the compound represented byformula (1b) in a suitable solvent. The compound represented by formula(1a) can be produced, for example, by the method disclosed in Pharmazie(1988), 43 (2), 86-90 and may be an acid addition salt with an inorganicacid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid, and phosphoric acid, or an acid additionsalt with an organic acid, such as formic acid, acetic acid, propionicacid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleicacid, lactic acid, malic acid, citric acid, tartaric acid, carbonicacid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, andglutamic acid. The compound represented by formula (1b) may be acommercially available product or may be obtained by producing itaccording to a known method, for example, the method disclosed inAngewandte Chemie, International Edition (2001), 40 (14), 2708-2710.

The solvent used in reaction scheme 1 is not particularly limited aslong as it is inert to the reaction, and examples of the solvent includeethers, such as diethyl ether and tetrahydrofuran; esters, such as ethylacetate and butyl acetate; halogenated hydrocarbons, such as methylenechloride and chloroform; aromatic hydrocarbons, such as benzene,toluene, and chlorobenzene; aprotic polar solvents, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, andacetonitrile; and alkylketones, such as acetone and methyl ethyl ketone.These may be used alone or in a combination of two or more. In thisreaction, an acid may be added. The acid is preferably hydrochloricacid, sulfuric acid, methanesulfonic acid, or paratoluenesulfonic acid,and may be preferably used in an amount of about 1- to about 2-foldmolar amount based on the compound represented by formula (1a)

In this reaction, the compound represented by formula (1b) is used in anamount of about 1- to about 20-fold molar amount, and preferably about1- to about 5-fold molar amount, based on the compound represented byformula (1a). As the solvent, the compound represented by formula (1b)may be used. The reaction temperature is about 50 to about 200° C., andpreferably about 80 to about 120° C. The reaction proceedsadvantageously in a reaction time of about 1 to about 240 hours.

If one or more asymmetric carbons are present in the compound (I), whichis useful as an active ingredient of the medicine of the presentinvention, optical isomers due to asymmetric carbon atoms (enantiomersand diastereomers) and other isomers may be present. The presentinvention encompasses isomers that have been isolated, and mixturesthereof.

The compound (I), which is useful as an active ingredient of themedicine of the present invention, encompasses pharmaceuticallyacceptable prodrugs. Pharmaceutically acceptable prodrugs are compoundshaving functional groups that can be converted, under chemicalconditions, such as solvolysis, or under physiological conditions, intoamino, hydroxyl, carboxyl, carbonyl, or like functional groups of thecompound (I), which is an active ingredient of the medicine of thepresent invention. Representative functional groups of prodrugs includethe groups mentioned in “Iyakuhin no Kaihatsu [Development ofPharmaceuticals],” Vol. 7, pp. 163-198, Hirokawa Publishing (1990).

The compound (I), which is useful as an active ingredient of themedicine of the present invention, may form an acid addition salt. Sucha salt is included in the present invention insofar as it ispharmaceutically acceptable. Specific examples thereof include acidaddition salts with inorganic acids, such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid, or organic acids, such as formic acid, acetic acid,propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,maleic acid, lactic acid, malic acid, citric acid, tartaric acid,carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonicacid, and glutamic acid.

The present invention further encompasses the hydrates, solvates, andcrystal polymorphs of the compound (I), which is useful as an activeingredient of the medicine of the present invention, andpharmaceutically acceptable salts thereof.

When a pharmaceutical composition contains the acetic acid estercompound or a salt thereof of the present invention, a pharmaceuticalcarrier can be added, if required, thereby forming a suitable dosageform according to prevention or treatment purposes. Examples of thedosage form include oral preparations, injections, suppositories,ointments, patches, and the like. Of these, oral preparations arepreferable. Such dosage forms can be formed by common preparationmethods known to persons skilled in the art.

As the pharmaceutical carrier, various organic or inorganic carriermaterials commonly used as preparation materials may be blended as anexcipient, binder, disintegrant, lubricant, or colorant in solidpreparations; or as a solvent, solubilizing agent, suspending agent,isotonizing agent, buffer, or soothing agent in liquid preparations.Moreover, a pharmaceutical preparation additive, such as an antiseptic,antioxidant, colorant, sweetener, and stabilizer, may also be used, ifrequired.

Oral solid preparations can be prepared as follows. An excipient,optionally together with a binder, disintegrant, lubricant, colorant,sweetening/flavoring agent, or the like, is added to the compound of thepresent invention to produce tablets, coated tablets, granules, powders,capsules, or the like, using an ordinary method.

Examples of excipients include lactose, sucrose, D-mannitol, glucose,starch, calcium carbonate, kaolin, microcrystalline cellulose, silicicacid anhydride, and the like.

Examples of binders include water, ethanol, 1-propanol, 2-propanol,simple syrup, liquid glucose, liquid α-starch, liquid gelatin,D-mannitol, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac,calcium phosphate, polyvinylpyrrolidone, and the like.

Examples of disintegrants include dry starch, sodium alginate, agarpowder, sodium hydrogen carbonate, calcium carbonate, sodium laurylsulfate, stearic acid monoglyceride, lactose, and the like.

Examples of lubricants include purified talc, sodium stearate, magnesiumstearate, borax, polyethylene glycol, and the like.

Examples of colorants include titanium oxide, iron oxide, and the like.

Examples of sweetening/flavoring agents include sucrose, wild orangepeel, citric acid, tartaric acid, and the like.

Oral liquid preparations can be produced as follows. Asweetening/flavoring agent, buffer, stabilizer, or the like, is added tothe compound of the present invention to produce an internal liquidmedicine, a syrup, an elixir, or the like, using an ordinary method. Inthis case, sweetening/flavoring agents as described above are usable.Examples of buffers include sodium citrate and the like, and examples ofstabilizers include tragacanth, gum arabic, gelatin, and the like. Ifnecessary, an enteric coating or a coating to increase the persistenceof effects can be provided by methods known for oral preparations.Examples of coating agents include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80 (registered trademark), and the like.

Injections can be prepared as follows. A pH adjuster, buffer,stabilizer, isotonizing agent, topical anesthetic, or the like, is addedto the compound of the present invention to produce a subcutaneousinjection, an intramuscular injection, or an intravenous injection usingan ordinary method. Examples of pH adjusters and buffers usable in thiscase include sodium citrate, sodium acetate, sodium phosphate, and thelike. Examples of stabilizers include sodium pyrosulfite, EDTA,thioglycolic acid, thiolactic acid, and the like. Examples of topicalanesthetics include procaine hydrochloride, lidocaine hydrochloride, andthe like. Examples of isotonizing agents include sodium chloride,glucose, D-mannitol, glycerin, and the like.

Suppositories can be prepared as follows. A pharmaceutical carrier knownin the art, such as polyethylene glycol, lanolin, cacao butter, or fattyacid triglyceride, is added to the compound of the present invention,optionally together with a like surfactant such as Tween 80 (registeredtrademark), followed by production using an ordinary method.

Ointments can be prepared as follows. An ordinary base, stabilizer,wetting agent, preservative, or the like, is added as required to thecompound of the present invention, and mixed and formulated using anordinary method. Examples of bases include liquid paraffin, whitepetrolatum, white beeswax, octyldodecyl alcohol, paraffin, and the like.Examples of preservatives include methyl parahydroxybenzoate, ethylparahydroxybenzoate, propyl parahydroxybenzoate, and the like.

Patches can be prepared by coating a general support with the aboveointment, cream, gel, paste, or the like, using an ordinary method.Examples of supports include woven or nonwoven fabrics made from cotton,staple fibers, and chemical fibers; and films and foam sheets of softvinyl chloride, polyethylene, and polyurethane.

The amount of the compound of the present invention to be contained insuch a dosage unit form varies depending on the condition of the patientor on the dosage form. The desirable amount in one dosage unit form istypically about 0.05 to about 1,000 mg in the case of an oralpreparation, about 0.01 to about 500 mg in the case of an injection, andabout 1 to about 1,000 mg in the case of a suppository.

The daily dose of a medicine in such a dosage form depends on thecondition, body weight, age, gender, or the like, of the patient. Forexample, the daily dose for an adult (body weight: 50 kg) may begenerally about 0.05 to about 5,000 mg, and preferably 0.1 to 1,000 mg,and is preferably administered in one dose or in two to three divideddoses per day.

Administration of a medicine containing the compound of the presentinvention is useful, for example, in mammals, and in particular humans,for preventing or treating a disease that is expected to be amelioratedby an increase in intraurethral pressure. Examples of diseases that canbe treated, prevented, or ameliorated with a medicine containing thecompound of the present invention include stress urinary incontinence,urge urinary incontinence, mixed urinary incontinence, and urinaryincontinence after an operation to remove the entire prostate gland.Further, a medicine containing the compound of the present invention isalso useful for frequent urination and urinary incontinence inneurogenic bladder, nervous bladder, unstable bladder, bladderirritation (chronic cystitis and chronic prostatitis), or the like;urinary urgency and frequent urination in overactive bladder;cardiovascular disease; irritable bowel syndrome; and climactericdisorder.

EXAMPLES

Examples and a Test Example are given below to illustrate the presentinvention in more detail; however, the present invention is not limitedto these Examples.

Reference Example 1 4-Piperidinyl 2-chloro-2,2-diphenylacetatehydrochloride

Thionyl chloride (3.1 ml, 42.1 mmol) and several drops ofdimethylformamide were added to 4-piperidinyl2-hydroxy-2,2-diphenylacetate hydrochloride (3.00 g, 8.62 mmol) obtainedaccording to the method disclosed in the document Pharmazie (1988), 43(2), 86-90, and the mixture was stirred for 2 hours at 80° C. Thereaction mixture was allowed to cool, and then concentrated underreduced pressure to give 4-piperidinyl 2-chloro-2,2-diphenylacetatehydrochloride. This compound was used for the next reaction withoutpurification.

Example 1 4-Piperidinyl 2,2-diphenyl-2-(propoxy-2,2,3,3,3-d5)acetatehydrochloride

To 4-piperidinyl 2-chloro-2,2-diphenylacetate hydrochloride obtained inReference Example 1, n-propanol-2,2,3,3,3-d5 (2.0 g, 34.5 mmol) wasadded, and the mixture was stirred while heating under reflux for 100hours. The reaction mixture was allowed to cool, and then concentratedunder reduced pressure. The precipitated solid was collected byfiltration, thereby obtaining crude crystals. Subsequently, the obtainedcrude crystals were recrystallized using ethyl acetate and methyl ethylketone to give 4-piperidinyl2,2-diphenyl-2-(propoxy-2,2,3,3,3-d5)acetate hydrochloride (2.27 g, 66%)as a white solid.

Example 2 4-Piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetatehydrochloride

Following the procedure of Example 1, n-propanol-1,1,2,2,3,3,3-d7 wasused instead of n-propanol-2,2,3,3,3-d5, thereby obtaining 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetate hydrochloride as awhite solid.

Example 3 4-Piperidinyl 2,2-diphenyl-2-(propoxy-1,1-d2)acetatehydrochloride

Following the procedure of Example 1, n-propanol-1,1-d2 was used insteadof n-propanol-2,2,3,3,3-d5, thereby obtaining 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1-d2)acetate hydrochloride as a white solid.

Example 4 4-Piperidinyl 2,2-diphenyl-2-(propoxy-2,2-d2)acetatehydrochloride

Following the procedure of Example 1, n-propanol-2,2-d2 was used insteadof n-propanol-2,2,3,3,3-d5, thereby obtaining 4-piperidinyl2,2-diphenyl-2-(propoxy-2,2-d2)acetate hydrochloride as a white solid.

Example 5 4-Piperidinyl 2,2-diphenyl-2-(propoxy-3,3,3-d3)acetatehydrochloride

Following the procedure of Example 1, n-propanol-3,3,3-d3 was usedinstead of n-propanol-2,2,3,3,3-d5, thereby obtaining 4-piperidinyl2,2-diphenyl-2-(propoxy-3,3,3-d3)acetate hydrochloride as a white solid.

Example 6 4-Piperidinyl 2,2-diphenyl-2-(propoxy-1,1,2,2-d4)acetatehydrochloride

Following the procedure of Example 1, n-propanol-1,1,2,2-d4 was usedinstead of n-propanol-2,2,3,3,3-d5, thereby obtaining 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1,2,2-d4)acetate hydrochloride as a whitesolid.

TABLE 1 Example R 1H-NMR (DMSO-d6) δ (ppm) m.p. (° C.) 1 —CH₂—CD₂—CD₃1.63-1.68 (m, 2H), 1.91-1.98 (m, 2H), 139-140 2.78-2.86 (m, 2H),2.95-3.04 (m, 2H), 3.11 (s, 2H) 5.02-5.08 (m, 1H), 7.30-7.40 (m, 10H),8.65 (brs, 1H) 2 —CD₂—CD₂—CD₃ 1.62-1.71 (m, 2H), 1.90-1.98 (m, 2H),137-139 2.78-2.85 (m, 2H), 2.95-3.04 (m, 2H), 5.01-5.08 (m, 1H),7.30-7.40 (m, 10H), 8.72 (brs, 1H) 3 —CD₂—CH₂—CH₃ 0.86 (t, 3H, J = 7.6Hz), 1.50 (q, 2H, J = 7.6 Hz), 139-141 1.60-1.70 (m, 2H), 1.89-1.98 (m,2H), 2.77-2.87 (m, 2H), 2.95-3.06 (m, 2H), 5.02-5.08 (m, 1H), 7.30-7.40(m, 10H), 8.65 (brs, 1H) 4 —CH₂—CD₂—CH₃ 0.84 (s, 3H), 1.60-1.71 (m, 2H),1.89-2.00 (m, 138-140 2H), 2.76-2.86 (m, 2H) 2.95-3.04 (m, 2H), 3.11 (s,2H) 5.02-5.08 (m 1H), 7.30-7.40 (m, 10H), 8.80 (brs, 1H) 5 —CH₂—CH₂—CD₃1.47-1.52 (m, 2H), 1.60-1.70 (m, 2H), 138-140 1.89-1.98 (m, 2H),2.78-2.86 (m, 2H), 2.95-3.10 (m, 2H), 3.10-3.15 (m, 2H) 5.02-5.08 (m,1H), 7.30-7.40 (m, 10H), 8.67 (brs, 1H) 6 —CD₂—CD₂—CH₃ 0.84 (s, 3H),1.60-1.71 (m, 2H), 1.89-2.00 (m, 137-139 2H), 2.76-2.86 (m, 2H),2.95-3.04 (m, 2H), 3.11 (s, 2H) 5.02-5.08 (m, 1H), 7.30-7.40 (m, 10H),8.80 (brs, 1H)

Test Example 1

1. Test Method

The compounds of the present invention and comparative compounds wereindividually orally administered in an amount of 3 mg/kg to 11-week-oldfemale SD rats (test substance-administration groups, n=8 for eachgroup), and distilled water was orally administered as the control to11-week-old female SD rats (solvent administration group, n=8). As thecomparative compounds, 4-(1-methylpiperidyl)2,2-diphenyl-2-propoxyacetate (Comparative Example 1),4-(1-methylpiperidyl) 2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetate(Comparative Example 2), which is a deuterated compound of ComparativeExample 1, and 4-piperidyl 2,2-diphenyl-2-propoxyacetate (ComparativeExample 3), synthesized according to Patent Literatures 1 to 3,respectively, were used.

Seven and a half hours after administration, each rat was anesthetizedby intraperitoneal administration of 1.2 g/kg of urethane. Thereafter,the ureters and the area between the urethra and the bladder wereligated, and a vesical fistula catheter and a catheter for measuringintraurethral pressure were inserted and indwelled in the bladder andthe urethra. The catheter for measuring intraurethral pressure wasinserted from the external urethral orifice. The other end of eachcatheter was connected to a corresponding pressure transducer branchedinto two directions via a corresponding three-way stopcock, and theremaining connecting portion of each three-way stopcock was connected toa corresponding syringe set in a continuous injection device.Intravesical pressure and intraurethral pressure were recorded via apolygraph connected with the pressure transducers. After the operation,physiological saline is injected into the bladder using the microsyringe pump connected to the bladder, and the injection was stoppedwhen rhythmic bladder contraction was observed. Physiological saline wasinjected into the urethra using the micro syringe pump connected to theurethra at 3 mL/hr, and the changes in intraurethral pressure associatedwith the rhythmic contraction were recorded.

2. Evaluation Item and Statistical Analysis

The mean value of urethral baseline pressure for each rat, i.e.,intraurethral pressure in a state in which the bladder does notcontract, for 30 minutes after 8 hours from the administration, wascalculated. The mean values of the urethral baseline pressure for thesolvent administration group and the test substance-administrationgroups were calculated, and the results were indicated as mean±SE. AStudent's t-test was used for the comparison between the solventadministration group and the test substance-administration groups.

3. Results

FIG. 1 shows the urethral baseline pressure of the solventadministration group and test substance-administration groups. Thecomparative compounds did not have a significant effect on the urethralbaseline pressure, whereas the compounds of the present invention showedsignificantly high urethral baseline pressure. Since decrease inurethral baseline pressure is believed to be a cause of stress urinaryincontinence, the compounds of the present invention are useful as aprophylactic or therapeutic agent for a disease that is expected to beameliorated by an increase in intraurethral pressure, such as stressurinary incontinence.

The invention claimed is:
 1. A method for increasing intraurethralpressure in a subject, the method comprising: administering to thesubject an effective amount of an acetic acid ester compound accordingrepresented by the following formula or a salt thereof,

wherein R represents a deuterated lower alkyl that is straight orbranched C₁-C₆ alkyl, wherein R is deuterated above natural abundance.2. The method of claim 1, wherein R represents deuterated straight C₁₋₆alkyl.
 3. The method of claim 1, wherein R represents n-propyl in which2 to 7 of the hydrogen atoms are replaced by deuterium.
 4. The method ofclaim 1, wherein R represents propyl-2,2,3,3,3-d5,propyl-1,1,2,2,3,3,3-d7, propyl-1,1-d2, propyl-2,2-d2, propyl-3,3,3-d3,or propyl-1,1,2,2-d4.
 5. The method of claim 1, wherein the acetic acidester compound is selected from the group consisting of the following(a) to (f), or a salt thereof: (a) 4-piperidinyl2,2-diphenyl-2-(propoxy-2,2,3,3,3-d5)acetate, (b) 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetate, (c) 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1-d2)acetate, (d) 4-piperidinyl2,2-diphenyl-2-(propoxy-2,2-d2)acetate, (e) 4-piperidinyl2,2-diphenyl-2-(propoxy-3,3,3-d3)acetate, and (f) 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1,2,2-d4)acetate.
 6. The method of claim 1,wherein the acetic acid ester compound is isolated and purified.
 7. Themethod of claim 1, wherein the subject has been diagnosed with a diseasethat is expected to be ameliorated by an increase in intraurethralpressure, or is at risk of developing a disease that is expected to beameliorated by an increase in intraurethral pressure.
 8. The method ofclaim 1, wherein the disease is urinary incontinence.
 9. The method ofclaim 8, wherein the disease is stress urinary incontinence.
 10. Themethod of claim 8, wherein the disease is urge urinary incontinence. 11.The method of claim 8, wherein the disease is mixed urinaryincontinence.
 12. The method of claim 8, wherein the disease is urinaryincontinence after an operation to remove the prostate.
 13. The methodof claim 1, wherein the subject has been diagnosed with urinaryincontinence, or is at risk of developing urinary incontinence.
 14. Amethod for treating urinary incontinence in a subject in need thereof,the method comprising: administering to the subject an effective amountof an acetic acid ester compound according represented by the followingformula or a salt thereof,

wherein R represents a deuterated lower alkyl that is straight orbranched C₁-C₆ alkyl, wherein R is deuterated above natural abundance.15. The method of claim 14, wherein R represents deuterated straightC₁₋₆ alkyl.
 16. The method of claim 14, wherein R represents n-propyl inwhich 2 to 7 of the hydrogen atoms are replaced by deuterium.
 17. Themethod of claim 14, wherein R represents propyl-2,2,3,3,3-d5,propyl-1,1,2,2,3,3,3-d7, propyl-1,1-d2, propyl-2,2-d2, propyl-3,3,3-d3,or propyl-1,1,2,2-d4.
 18. The method of claim 14, wherein the aceticacid ester compound is selected from the group consisting of thefollowing (a) to (f), or a salt thereof: (a) 4-piperidinyl2,2-diphenyl-2-(propoxy-2,2,3,3,3-d5)acetate, (b) 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1,2,2,3,3,3-d7)acetate, (c) 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1-d2)acetate, (d) 4-piperidinyl2,2-diphenyl-2-(propoxy-2,2-d2)acetate, (e) 4-piperidinyl2,2-diphenyl-2-(propoxy-3,3,3-d3)acetate, and (f) 4-piperidinyl2,2-diphenyl-2-(propoxy-1,1,2,2-d4)acetate.
 19. The method of claim 14,wherein the urinary incontinence is ameliorated by an increase inintraurethral pressure.
 20. The method of claim 14, wherein the urinaryincontinence is stress urinary incontinence.
 21. The method of claim 14,wherein the urinary incontinence is urge urinary incontinence.
 22. Themethod of claim 14, wherein the urinary incontinence is mixed urinaryincontinence.
 23. The method of claim 14, wherein the urinaryincontinence is urinary incontinence after an operation to remove asubject's prostate.